Targeting HIV-1 RNase H:N'-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants
Targeting HIV-1 RNase H:N'-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants
复制标题
DOI：
10.3390/v12070729
复制
发表时间：
2020-07-01
期刊：
影响因子：
4.7
通讯作者：
Tramontano, Enzo
中科院分区：
文献类型：
--
作者：
Corona, Angela;Ballana, Ester;Tramontano, Enzo
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action ofN'-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound13), anN-acylhydrazone derivative that inhibited viral replication (EC50= 10 mu M), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound13targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound13binds within the RNase H domain in a position different from other selective RNase H inhibitors; site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound13can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants.
